Tolterodine (3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine) is a muscarinic receptor antagonist for the treatment of overactive bladder including urinary incontinence. In the body it is converted to a hydroxy metabolite 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol (hydroxytolterodine, HT), which is also an active molecule.

Hydroxytolterodine (HT) was firstly prepared in WO 94/011337 in a synthesis, which is extremely long. Similar approach was repeated in WO 99/058478 and optimised in WO 07/138,440, WO 07/144,097 and WO 07/144,091. Described synthetic variations involve synthesis via bromo substituted lactone derivative (the bromo process) in 9 to 11 steps, in which some steps include reagents, unwanted in a routine industrial process such as Grignard reagents and aluminium hydrides.
The bromo process is shown in three partial schemes.



Several approaches how to simplify the first published process were later developed. An approach via hydrocoumarines (the lactone route), known from preparations of tolterodine was applied to intermediates with different para phenol substituents. The approaches are summarized in Scheme 4 in which transformations shown by arrows can be multistep and the preparations differ each to each by different para phenol substituents R(COOR′, COOH, halo, Me, CH2OH), using or omitting protective groups, and in which step the reduction is carried out. The preparations are described at least but not limited in WO 89/006644, WO 01/096279, Org. Lett. 7, 2285 (2005), WO 07/144,097.

The shortest modification of above described lactone process is described in WO 07/138,440. In this process the lactol is formed in one step by cinnamaldehyde. The lactol is then transformed further into HT by reaction with diisopropylamine and hydrogen gas in the presence of Pd/C. The formation of lactol suffers of low yield and by-products so it must be accomplished by use of amines and isolation of intermediate aminal ethers what makes process longer. Major issues with this synthesis are a use of heavy metals and of hydrogen gas. Synthesis is shown in Scheme 5.

Some other synthetic routes use reagents that are less common for industrial purposes. Such routes are described in WO 94/011337 and WO 02/004399. The former involves a Heck reaction step, which is followed by organolithium coupling in the presence of copper salt and a reduction step (the Heck-cuprate process, Scheme 6).

The latter describes a reaction with phenylacetylene (the phenylacetylene route, Scheme 7) in the presence of SnCl4 and a reaction with carbon monoxide and diisopropylamine in the presence of BINAP/Pd catalyst. Both procedures use hydrogen gas, heavy metals, and strong reducing agents, toxic and potentially hazardous reagents.

Another synthesis is described in WO 05/012227. HT is prepared by oxidation of tolterodine. An oxidation of toluenic methyl group is not easy and demands protection of phenolic hydroxy group what essentially prolongs the synthesis of HT.

The shortest synthesis of tolterodine is described in WO 07/017,544 and WO 07/147,547 and is shown in Scheme 9. Excess of p-cresol reacted in a neat or a concentrated strong acid such as methansulphonic, hydrobromic, sulfuric, perchloric or p-toluenesulfonic acid with N,N-diisopropyl-3-phenylprop-2-en-1-amine (N,N-diisopropyl cinnamylamine, DIPCA) to give tolterodine in only one step.

A skilled person might try to apply this synthetic approach also to the preparation of HT. But surprisingly a reaction of p-hydroxybenzyl alcohol with DIPCA completely fails. Furthermore, the failure was found also applying the reaction with phenols, para substituted with groups, convertible to hydroxymethyl group, such as p-hydroxybenzoic acid, p-hydroxybenzoic esters, p-cyanophenol and p-hydroxybenzaldehyde and also with their corresponding O-protected analogues. The reaction could be applied only on halo derivatives but a transformation of halo to hydroxymethyl group needs Grignard reaction and a protection of phenolic group as shown in Schemes 1-3, that considerably prolongs the synthesis.
Possible transformations of some groups to the hydroxymethyl group of HT are listed below and are summarized in Scheme 10.
ahalogenGrignard reaction, protection of phenol, reductionsbalkoxycarbonylprotection of phenol, anhydrous reductionsccarboxyprotection of phenol, anhydrous reductions,optionally transformation to estersdcyanodouble reduction or hydrolysis + reductioneformylnon-anhydrous one step reduction

A skilled person might try to synthesize HT by way of reduction of 3-(5-formyl-2-hydroxyphenyl)-N,N-diisopropyl-3-phenylpropylamine (PHB). The synthesis of PHB by reacting DIPCA and p-hydroxybenzaldehyde in the presence of a strong acid has been disclosed in WO 07/147,547. However, the disadvantages of said synthesis of PHB are very low yields (e.g. 8%).
Therefore, there is still a need for a short synthesis of 3-(5-formyl-2-hydroxyphenyl)-N,N-diisopropyl-3-phenylpropylamine (PHB) with higher yields for an efficient synthesis of hydroxytolterodine (HT).